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International Journal of Molecular... Jan 2022Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and...
Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and structural analysis of 4 novel variants located in the gene coding for fibrinogen Bβ chain-heterozygous missense BβY416C and BβA68S, homozygous nonsense BβY345*, and heterozygous nonsense BβW403* mutations. The cases were identified by coagulation screening tests and further investigated by various methods. Fibrin polymerization had abnormal development with decreased maximal absorbance in all patients. Plasmin-induced fibrin degradation revealed different lytic phases of BβY416C and BβW403* than those of the control. Fibrinopeptide cleavage measured by reverse phase high pressure liquid chromatography of BβA68S showed impaired release of fibrinopeptide B. Morphological properties, studied through scanning electron microscopy, differed significantly in the fiber thickness of BβY416C, BβA68S, and BβW403*, and in the fiber density of BβY416C and BβW403*. Finally, homology modeling of BβA68S showed that mutation caused negligible alternations in the protein structure. In conclusion, all mutations altered the correct fibrinogen function or structure that led to congenital fibrinogen disorders.
Topics: Adolescent; Afibrinogenemia; Aged; Blood Coagulation; Blood Coagulation Tests; DNA Mutational Analysis; Female; Fibrinogen; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant, Newborn; Male; Middle Aged; Models, Molecular; Mutation; Phenotype; Protein Conformation; Structure-Activity Relationship
PubMed: 35054908
DOI: 10.3390/ijms23020721 -
BMJ Case Reports Jul 2019Patients with multiple myeloma (MM) are at risk for acquired dysfibrinogenemia resulting in laboratory abnormalities and/or bleeding complications. We describe a...
Patients with multiple myeloma (MM) are at risk for acquired dysfibrinogenemia resulting in laboratory abnormalities and/or bleeding complications. We describe a 63-year-old man who presented with bleeding diathesis in the presence of a low fibrinogen activity level with a normal fibrinogen antigen level. Further studies revealed elevated levels of lambda free light chains, and he was diagnosed with MM. Despite initiating treatment with bortezomib/dexamethasone, he continued to have recurrent bleeds along with hypofibrinogenaemia, prompting a switch to carfilzomib/dexamethasone. The patient responded with improvement in bleeding symptoms, normalisation of fibrinogen activity and a decrease in serum free light chains.
Topics: Afibrinogenemia; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Substitution; Hemorrhage; Humans; Immunoglobulin lambda-Chains; Male; Middle Aged; Multiple Myeloma; Oligopeptides
PubMed: 31320370
DOI: 10.1136/bcr-2019-229312 -
Transfusion Jun 2021Fibrinogen concentrates and cryoprecipitate are currently used for fibrinogen supplementation in bleeding patients with dysfibrinogenemia. Both products provide an...
BACKGROUND
Fibrinogen concentrates and cryoprecipitate are currently used for fibrinogen supplementation in bleeding patients with dysfibrinogenemia. Both products provide an abundant source of fibrinogen but take greater than 10 min to prepare for administration. Fibrinogen concentrates lack coagulation factors (i.e., factor VIII [FVIII], factor XIII [FXIII], von Willebrand factor [VWF]) important for robust hemostatic function. Cryoprecipitate products contain these factors but have short shelf lives (<6 h). Pathogen reduction (PR) of cryoprecipitate would provide a shelf-stable immediately available adjunct containing factors important for rescuing hemostatic dysfunction.
STUDY DESIGN AND METHODS
Hemostatic adjunct study products were psoralen-treated PR-cryoprecipitated fibrinogen complex (PR-Cryo FC), cryoprecipitate (Cryo), and fibrinogen concentrates (FibCon). PR-Cryo FC and Cryo were stored for 10 days at 20-24°C. Adjuncts were added to coagulopathies (dilutional, 3:7 whole blood [WB]:normal saline; or lytic, WB + 75 ng/ml tissue plasminogen activator), and hemostatic function was assessed by rotational thromboelastometry and thrombin generation.
RESULTS
PR of cryoprecipitate did not reduce levels of FVIII, FXIII, or VWF. PR-Cryo FC rescued dilutional coagulopathy similarly to Cryo, while generating significantly more thrombin than FibCon, which also rescued dilutional coagulopathy. Storage out to 10 days at 20-24°C did not diminish the hemostatic function of PR-Cryo FC.
DISCUSSION
PR-Cryo FC provides similar and/or improved hemostatic rescue compared to FibCon in dilutional coagulopathies, and this rescue ability is stable over 10 days of storage. In hemorrhaging patients, where every minute delay is associated with a 5% increase in mortality, the immediate availability of PR-Cryo FC has the potential to improve outcomes.
Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Safety; Factor VIII; Fibrinogen; Hemostasis; Hemostatics; Humans; Sterilization
PubMed: 33755208
DOI: 10.1111/trf.16376 -
Balkan Medical Journal Jan 2021
Topics: Aged; Aneurysm, Infected; Cyclophosphamide; Female; Fever; Glomerulonephritis, IGA; Hematoma; Humans; Sepsis; Tomography, X-Ray Computed
PubMed: 32720494
DOI: 10.4274/balkanmedj.galenos.2020.2020.5.208 -
Hamostaseologie Dec 2023
PubMed: 38096836
DOI: 10.1055/a-2218-6919 -
Cureus Mar 2021Multiple myeloma is a neoplastic disorder of plasma cells. An abnormal coagulation profile, though commonly seen in multiple myeloma, can rarely manifest as...
Multiple myeloma is a neoplastic disorder of plasma cells. An abnormal coagulation profile, though commonly seen in multiple myeloma, can rarely manifest as life-threatening hemorrhagic complications. Bleeding tendencies in multiple myeloma can be explained by a variety of mechanisms such as dysfibrinogenemia, paraprotein-induced platelet dysfunction, shortened platelet survival, damage to the vascular endothelium, and acquired von-Willebrand syndrome. Herein, we report a 61-year-old female who presented with the signs and symptoms of hemorrhagic shock with multiple myeloma, which remained refractory to a massive transfusion protocol. Her condition stabilized when she was started on dexamethasone and antifibrinolytic infusion targeting acquired dysfibrinogenemia. To the best of our knowledge, hemorrhagic shock secondary to dysfibrinogenemia is an unusual phenomenon in multiple myeloma.
PubMed: 33880309
DOI: 10.7759/cureus.13990 -
Hamostaseologie Dec 2023Inherited dysfibrinogenemia is a qualitative defect of fibrinogen caused by various mutations among three fibrinogen genes. Dysfibrinogenemia can be associated with...
INTRODUCTION
Inherited dysfibrinogenemia is a qualitative defect of fibrinogen caused by various mutations among three fibrinogen genes. Dysfibrinogenemia can be associated with an increased risk of thrombosis, bleeding, or both. Here, we report a 36-year-old female with dysfibrinogenemia who experienced two successful pregnancies under thromboprophylaxis after cerebral venous sinus thrombosis (CVST).
PATIENTS AND METHODS
In addition to plasmatic coagulation tests, fibrinogen genes , , and were screened using direct genomic DNA sequencing. The structural-functional implications of the detected mutation were analyzed in silico.
RESULTS
Inherited dysfibrinogenemia was diagnosed in an index patient after CVST in a risk situation. Anticoagulation with warfarin was stopped after 12 months when the first pregnancy was planned. Pregnancy and spontaneous delivery (2020) was uncomplicated. A second pregnancy was interrupted because of acute cytomegalovirus infection and the third pregnancy was successful in 2022. Pregnancies were accompanied by thromboprophylaxis with enoxaparin 40 mg once daily until 6 weeks postpartum. Substitution of fibrinogen has not become necessary in the index patient so far. Genetic analysis revealed a novel missense mutation (p. Arg510Cys) in the gene ("fibrinogen Bonn") in the index patient, as well as an asymptomatic sister, and their father who experienced recurrent pulmonary embolism. Surface exposure of wild-type Arg510 suggested the mutated Cys510 to form nonnative disulfide bonds with surface-exposed reactive cysteines from other plasma proteins like albumin leading to formation of aggregates and impaired fibrinolysis.
CONCLUSIONS
Fibrinogen Bonn might be associated with an increased risk of thrombosis, possibly due to impaired polymerization.
Topics: Pregnancy; Female; Humans; Adult; Fibrinogen; Anticoagulants; Venous Thromboembolism; Afibrinogenemia; Venous Thrombosis; Mutation; Thrombosis; Hemostatics
PubMed: 37442158
DOI: 10.1055/a-2094-7191 -
Frontiers in Medicine 2020A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months,...
A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months, the patient developed a severe bleeding disorder. The bleeding was due to fibrin polymerization defect that upon sequencing was shown to be dysfibrinogenemia Krakow III. Elimination of the mTor inhibitor ameliorated the clinical bleeding state.
PubMed: 33330551
DOI: 10.3389/fmed.2020.591546 -
TH Open : Companion Journal To... Jan 2022
PubMed: 35088022
DOI: 10.1055/s-0041-1740644 -
Research and Practice in Thrombosis and... Nov 2020Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder characterized by reduced levels (afibrinogenemia, hypofibrinogenemia) or dysfunctional fibrinogen...
BACKGROUND
Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder characterized by reduced levels (afibrinogenemia, hypofibrinogenemia) or dysfunctional fibrinogen (dysfibrinogenemia), for which fibrinogen supplementation is the mainstay treatment.
OBJECTIVES
To assess the efficacy and safety of human fibrinogen concentrate (FCH) in patients with CFD.
METHODS
This was a multicenter, noninterventional, retrospective cohort study with a 12-month prospective follow-up period in the United States and Canada. Individuals with CFD who received FCH for the treatment of bleeding, perioperative hemostasis, or prophylaxis were included. Data were collected retrospectively from medical records and every 3 months during the prospective period. Hemostatic efficacy was rated by the investigators as effective or ineffective using a 4-point efficacy scale. Annualized bleeding rate (ABR) was summarized for patients who received FCH for routine prophylaxis.
RESULTS
Twenty-two patients were enrolled. FCH treatment was rated effective in treating ≥97.0% of bleeding events, in the retrospective and prospective periods. FCH was effective for perioperative hemostasis in ≥97.5% of minor and major surgeries across both periods. In patients treated with FCH for routine prophylaxis, the median ABRs for the retrospective and prospective period were 1.4 and 1.3, respectively. One adverse event (AE), thrombosis of the right cephalic vein, was reported as related to FCH treatment and resolved with a short course of anticoagulant. No serious AEs related to FCH or deaths were reported.
CONCLUSIONS
In patients with CFD, FCH is a well-tolerated and effective treatment to achieve hemostasis during bleeding events and surgery and associated with infrequent bleeding events when used prophylactically.
PubMed: 33313470
DOI: 10.1002/rth2.12433